PITUITARY AND HYPOTHALAMUS

DEVELOPMENT OF THE PITUITARY GLAND

The pituitary gland, also termed the hypophysis , consists of two major components, the adenohypophysis and the neurohypophysis. The adenohypophysis (anterior lobe) is derived from the oral ectoderm, and the neurohypophysis (posterior lobe) is derived from the neural ectoderm of the floor of the forebrain.

A pouchlike recess—Rathke pouch—in the ectodermal lining of the roof of the stomodeum is formed by the fourth to fifth week of gestation and gives rise to the anterior pituitary gland. Rathke pouch extends upward to contact the undersurface of the forebrain and is then constricted by the surrounding mesoderm to form a closed cavity. The original connection between Rathke pouch and the stomodeum—known as the craniopharyngeal canal—runs from the anterior part of the pituitary fossa to the undersurface of the skull. Although it is usually obliterated, a remnant may persist in adult life as a “pharyngeal pituitary” embedded in the mucosa on the dorsal wall of the pharynx. The pharyngeal pituitary may give rise to ectopic hormone-secreting pituitary adenomas later in life.

Behind Rathke pouch, a hollow neural outgrowth extends toward the mouth from the floor of the third ventricle. This neural process forms a funnel-shaped sac—the infundibular process—that becomes a solid structure, except at the upper end where the cavity persists as the infundibular recess of the third ventricle. As Rathke pouch extends toward the third ventricle, it fuses on each side of the infundibular process and subsequently obliterates its lumen, which sometimes persists as Rathke cleft. The anterior lobe of the pituitary is formed from Rathke pouch, and the infundibular process gives rise to the adjacent posterior lobe (neurohypophysis). The neurohypophysis consists of the axons and nerve endings of neurons whose cell bodies reside in the supraoptic and paraventricular nuclei of the hypothalamus, forming a hypothalamic–neurohypophysial nerve tract that contains approximately 100,000 nerve fibers. Remnants of Rathke pouch may persist at the boundary of the neurohypophysis, resulting in small colloid cysts.

The anterior lobe also gives off two processes from its ventral wall that extend along the infundibulum as the pars tuberalis, which fuses to surround the upper end of the pituitary stalk. The cleft is the remains of the original cavity of the stomodeal diverticulum. The dorsal (posterior) wall of the cleft remains thin and fuses with the adjoining posterior lobe to form the pars intermedia. The pars intermedia remains intact in some species, but in humans, its cells become interspersed with those of the anterior lobe, and it develops the capacity to synthesize and secrete pro-opiomelanocortin (POMC) and corticotropin (adrenocorticotropic hormone [ACTH]). The part of the tuber cinereum that lies immediately above the pars tuberalis is termed the median eminence .

Both the adenohypophysis and the neurohypophysis are subdivided into three parts. The adenohypophysis consists of the pars tuberalis, a thin strip of tissue that surrounds the median eminence and the upper part of the neural stalk; the pars intermedia, the portion posterior to the cleft and in contact with the neurohypophysis; and the pars distalis (pars glandularis), the major secretory part of the gland. The neurohypophysis is composed of an expanded distal portion termed the infundibular process ; the infundibular stem (neural stalk); and the expanded upper end of the stalk, the median eminence of the tuber cinereum.

DIVISIONS OF THE PITUITARY GLAND AND RELATIONSHIP TO THE HYPOTHALAMUS

The pituitary gland (hypophysis) is composed of the neurohypophysis (posterior pituitary lobe) and adenohypophysis (anterior pituitary lobe). The neurohypophysis consists of three parts: the median eminence of the tuber cinereum, infundibular stem, and infundibular process (neural lobe). The adenohypophysis is likewise divided into three parts: the pars tuberalis, pars intermedia, and pars distalis (glandularis). The infundibular stem, together with portions of the adenohypophysis that form a sheath around it, is designated as the hypophysial (pituitary) stalk. The extension of neurohypophysial tissue up the stalk and into the median eminence of the tuber cinereum constitutes approximately 15% of the neurohypophysis. A low stalk section may leave enough of the gland still in contact with its higher connections in the paraventricular and supraoptic nuclei to prevent the onset of diabetes insipidus. Atrophy and disappearance of cell bodies in the supraoptic and paraventricular nuclei follow damage to their axons in the supraopticohypophysial tract. If the tract is cut at the level of the diaphragma sellae, only 70% of these cells are affected; if the tract is severed above the median eminence, about 85% of the cells will atrophy. Thus, approximately 15% of the axons terminate between these levels.

The main nerve supply, both functionally and anatomically, of the neurohypophysis is the hypothalamohypophysial tract in the pituitary stalk. It consists of two main parts: the supraopticohypophysial tract, running in the anterior or ventral wall of the stalk, and the tuberohypophysial tract in the posterior, or dorsal, wall of the stalk. The tuberohypophysial tract originates in the central and posterior parts of the hypothalamus from the paraventricular nucleus and from scattered cells and nuclei in the tuberal region and mamillary bodies. The supraopticohypophysial tract arises from the supraoptic and paraventricular nuclei. On entering the median eminence, it occupies a very superficial position, where it is liable to be affected by basal infections of the brain and granulomatous inflammatory processes. The tuberohypophysial tract in the dorsal region of the median eminence is smaller and consists of finer fibers. In the neural stalk, all the fibers congregate into a dense bundle lying in a central position, leaving a peripheral zone in contact with the pars tuberalis, which is relatively free of nerve elements. The hypothalamohypophysial tract terminates mainly in the neurohypophysis.

The hypothalamus has ill-defined boundaries. Anteroinferiorly, it is limited by the optic chiasm and optic tracts; passing posteriorly, it is bounded by the posterior perforated substance and the cerebral peduncles. On sagittal section, it can be seen to be separated from the thalamus by the hypothalamic sulcus on the wall of the third ventricle. Anteriorly, it merges with the preoptic septal region, and posteriorly, it merges with the tegmental area of the midbrain. Its lateral relations are the subthalamus and the internal capsule.

A connective tissue trabecula separates the posterior and anterior lobes of the pituitary; it also extends out into the anterior pituitary lobe for a variable distance as a vascular bed for the large-lumened artery of the trabecula. The embryonic cleft, which marks the site of the Rathke pouch within the gland, may be contained, in part, in this trabecula. It is easier to see in newborns and tends to disappear in later life. Colloid-filled follicles in the adult gland mark the site of the pars intermedia at the junction between the pars distalis and the neurohypophysis. This boundary may be quite irregular because fingerlike projections of adenohypophysial tissue are frequently found in the substance of the neurohypophysis.

BLOOD SUPPLY OF THE PITUITARY GLAND

The pituitary gland receives its arterial blood supply from two paired systems of vessels: from above come the right and left superior hypophysial arteries, and from below arise the right and left inferior hypophysial arteries. Each superior hypophysial artery divides into two main branches—the anterior and posterior hypophysial arteries passing to the hypophysial stalk. Communicating branches between these anterior and posterior superior hypophysial arteries run on the lateral aspects of the hypophysial stalk; numerous branches arise from this arterial circle. Some pass upward to supply the optic chiasm and the hypothalamus. Other branches, called infundibular arteries , pass either superiorly to penetrate the stalk in its upper part or inferiorly to enter the stalk at a lower level. Another important branch of the anterior superior hypophysial artery on each side is the artery of the trabecula, which passes downward to enter the pars distalis. The trabecula is a prominent, compact band of connective tissue and blood vessels lying within the pars distalis on either side of the midline. At its central end the trabecula is contiguous with the mass of connective tissue, which is interposed between the pars distalis and the lower infundibular stem. Peripherally, the components of the trabecula spread out to form a fibrovascular tuft. On approaching the lower infundibular stem, the artery of the trabecula gives off numerous straight parallel vessels to the superior portion of this area and thus constitutes the “superior artery of the lower infundibular stem.” The “inferior artery of the lower infundibular stem” is derived from the inferior hypophysial arterial system. The artery of the trabecula is of large caliber throughout its course; it gives off no branches to the epithelial tissue through which it passes. It is markedly tortuous and is always surrounded by connective tissue.

The inferior hypophysial arteries arise as a single branch from each internal carotid artery in its intracavernous segment. Near the junction of the anterior and posterior lobes of the pituitary, the artery gives off one or more tortuous vessels to the dural covering of the pars distalis and finally divides into two main branches—a medial and a lateral inferior hypophysial artery. The infundibular process is surrounded by an arterial ring formed by the medial and lateral branches of the paired inferior hypophysial arteries. From this arterial ring, branches are given off to the posterior lobe and to the lower infundibular stem. Components of the superior and inferior hypophysial arterial systems anastomose freely.

The epithelial tissue of the pars distalis receives no direct arterial blood. The sinusoids of the anterior lobe receive their blood supply from the hypophysial portal vessels, which arise from the capillary beds within the median eminence and the upper and lower portions of the infundibular stem. Blood is conveyed from this primary capillary network through hypophysial portal veins to the epithelial tissue of the anterior lobe. Here, a secondary plexus of the pituitary portal system is formed, leading to the venous dural sinuses, which surround the pituitary, and to the general circulation. Some of the long hypophysial portal veins run along the surface of the stalk, chiefly on its anterior and lateral aspects. Most of the long hypophysial portal vessels leave the neural tissue to run down within the pars tuberalis, but a few remain deep within the stalk until they reach the pars distalis. The short hypophysial portal veins are embedded in the tissue surrounding the lower infundibular stem. They supply the sinusoidal bed of the posterior part of the pars distalis, and the long portal veins supply its anterior and lateral regions.

Vascular tufts, comprising the primary capillary network in the median eminence and infundibular stem, are intimately related to the great mass of nerve fibers of the hypothalamo-hypophysial tract running in this region. On excitation, these nerve fibers liberate into the portal vessels, releasing hormones (e.g., growth hormone–releasing hormone, corticotropin-releasing hormone, gonadotropin-releasing hormone, thyrotropin-releasing hormone) and inhibitory factors (e.g., somatostatin, prolactin-inhibitory factor [dopamine]), which are conveyed to the sinusoids of the pars distalis. Extensive occlusion of the hypophysial portal vessels or of the capillary beds of the hypophysial stalk may lead to ischemic necrosis of the anterior pituitary because these hypophysial portal vessels are the only afferent channels to the sinusoids of the pars distalis.

ANATOMY AND RELATIONSHIPS OF THE PITUITARY GLAND

The pituitary gland is reddish-gray and ovoid, measuring about 12 mm transversely, 8 mm in its anterior-posterior diameter, and 6 mm in its vertical dimension. It weighs approximately 500 mg in men and 600 mg in women. It is contiguous with the end of the infundibulum and is situated in the hypophysial fossa of the sphenoid bone. A circular fold of dura mater, the diaphragma sellae, forms the roof of this fossa. In turn, the floor of the hypophysial fossa forms part of the roof of the sphenoid sinus. The diaphragma sellae is pierced by a small central aperture through which the pituitary stalk passes, and it separates the anterior part of the upper surface of the gland from the optic chiasm. The hypophysis is bound on each side by the cavernous sinuses and the structures that they contain. Inferiorly, it is separated from the floor of the fossa by a large, partially vacuolated venous sinus, which communicates freely with the circular sinus. The meninges blend with the capsule of the gland and cannot be identified as separate layers of the fossa. However, the subarachnoid space often extends a variable distance into the sella, particularly anteriorly, and may be referred to as a “partially empty sella” when seen on magnetic resonance imaging (MRI) (see Plate 1-12 ). In some cases of subarachnoid hemorrhage, the dorsal third of the gland may be covered with blood that has extended down into this space.

The hypothalamus is an important relation of the pituitary gland, both anatomically and functionally. This designation refers to the structures contained in the anterior part of the floor of the third ventricle and to those comprising the lateral wall of the third ventricle below and in front of the hypothalamic sulcus. The mamillary bodies are two round, white, pea-sized masses located side by side below the gray matter of the floor of the third ventricle in front of the posterior perforated substance. They form the posterior limits of the hypothalamus. At certain sites at the base of the brain, the arachnoid is separated from the pia mater by wide intervals that communicate freely with one another; these are called subarachnoid cisterns . As the arachnoid extends across between the two temporal lobes, it is separated from the cerebral peduncles by the interpeduncular cistern. Anteriorly, this space is continued in front of the optic chiasm as the chiasmatic cistern. Space-occupying lesions distort these cisterns.

The optic chiasm is an extremely important superior relation of the pituitary gland. It is a flat, somewhat quadrilateral bundle of optic nerve fibers situated at the junction of the anterior wall of the third ventricle with its floor. Its anterolateral angles are contiguous with the optic nerves, and its posterolateral angles are contiguous with the optic tracts. The lamina terminalis, which represents the cephalic end of the primitive neural tube, forms a thin layer of gray matter stretching from the upper surface of the chiasm to the rostrum of the corpus callosum. Inferiorly, the chiasm rests on the diaphragma sellae just behind the optic groove of the sphenoid bone. A small recess of the third ventricle, called the optic recess , passes downward and forward over its upper surface as far as the lamina terminalis. A more distant relationship is the pineal gland, which is a small, conical, reddish-gray body lying below the splenium of the corpus callosum. Rarely, ectopic pineal tissue occurs in the floor of the third ventricle and gives rise to tumors of that region. Compression of neighboring cranial nerves, other than the optic nerves, may occur if there is extensive cavernous sinus extension from a pituitary neoplasm (see Plate 1-24 ).

RELATIONSHIP OF THE PITUITARY GLAND TO THE CAVERNOUS SINUS

The sinuses of the dura mater are venous channels that drain the blood from the brain. The cavernous sinuses are so named because of their reticulated structure, being traversed by numerous interlacing filaments that radiate out from the internal carotid artery extending anteroposteriorly in the center of the sinuses. They are located astride and on either side of the body of the sphenoid bone and adjacent to the pituitary gland. Each opens behind into the superior and inferior petrosal sinuses (see Plate 3-10 ). On the medial wall of each cavernous sinus, the internal carotid artery is in close contact with the abducens nerve (VI). On the lateral wall are the oculomotor (III) and trochlear (IV) nerves and the ophthalmic and maxillary divisions of the trigeminal nerve (V). These structures are separated from the blood flowing along the sinus by the endothelial lining membrane. The two cavernous sinuses communicate with each other by means of two intercavernous sinuses. The anterior sinus passes in front of the pituitary gland and the posterior behind it. Together they form a circular sinus around the hypophysis. These channels are found between the two layers of dura mater that comprise the diaphragma sellae and are responsible for copious bleeding when this structure is incised when a transcranial surgical approach to the pituitary gland is used. Sometimes profuse bleeding from an inferior circular sinus is encountered in the transsphenoidal approach to the pituitary gland (see Plate 1-31 ).

The superior petrosal sinus is a small, narrow channel that connects the cavernous sinus with the transverse sinus. It runs backward and laterally from the posterior end of the cavernous sinus over the trigeminal nerve (V) and lies in the attached margin of the tentorium cerebelli and in the superior petrosal sulcus of the temporal bone. The cavernous sinus also receives the small sphenoparietal sinus, which runs anteriorly along the undersurface of the lesser wing of the sphenoid.

The intercavernous portion of the internal carotid artery runs a complicated course. At first, it ascends toward the posterior clinoid process; then it passes forward alongside the body of the sphenoid bone and again curves upward on the medial side of the anterior clinoid process. It perforates the dura mater that forms the roof of the sinus. This portion of the artery is surrounded by filaments of sympathetic nerves as it passes between the optic and oculomotor nerves. The hypophysial arteries are branches of the intercavernous segment of the internal carotid artery. The inferior branch supplies the posterior lobe of the pituitary gland, and the superior branch leads into the median eminence to start the hypophysial portal system to the anterior lobe.

The surgical approaches to the pituitary gland are designed to circumvent the major vascular channels and to avoid injury to the optic nerves and to the optic chiasm (see Plate 1-31 ).

RELATIONSHIPS OF THE SELLA TURCICA

The sella turcica—where the pituitary gland is located—is the deep depression in the body of the sphenoid bone. In adults, the normal mean anterior-posterior length is less than 14 mm, and the height from the floor to a line between the tuberculum sellae and the tip of the posterior clinoid is less than 12 mm.

To understand its relations, a more general description of the sphenoid bone is needed. Situated at the base of the skull in front of the temporal bones and the basilar part of the occipital bone, the sphenoid bone somewhat resembles a bat with its wings extended. It is divided into a median portion, or body, two great and two small wings extending outward from the sides of the body, and two pterygoid processes projecting below. The cubical body is hollowed out to form two large cavities, the sphenoidal air sinuses, which are separated from each other by a septum that is often oblique. The superior surface of the body articulates anteriorly with the cribriform plate of the ethmoid and laterally with the frontal bones. Most of the frontal articulation is with the small wing of the sphenoid bone. Behind the ethmoidal articulation is a smooth surface, slightly raised in the midline and grooved on either side, for the olfactory lobes of the brain. This surface is bound behind by a ridge, which forms the anterior border of a narrow transverse groove, the chiasmatic sulcus, above and behind which lies the optic chiasm. The groove ends on either side in the optic foramen, through which the optic nerve and ophthalmic artery enter into the orbital cavity.

Behind the chiasmatic sulcus is an elevation, the tuberculum sellae. Immediately posterior there is a deep depression, the sella turcica, the deepest part of which is called the hypophysial fossa. The anterior boundary of the sella turcica is completed by two small prominences, one on each side, called the middle clinoid processes. The posterior boundary of the sella is formed by an elongated plate of bone, the dorsum sellae, which ends at its superior angles as two tubercles, the posterior clinoid processes.

Behind the dorsum sellae is a shallow depression, the clivus, which slopes obliquely backward to continue as a groove on the basilar portion of the occipital bone. The lateral surfaces of the sphenoid body are united with the great wings and the medial pterygoid plates. Above the attachment of each great wing is a broad groove that contains the internal carotid artery and the cavernous sinus. The superior surface of each great wing forms part of the middle fossa of the skull. The internal carotid artery passes through the foramen lacerum, a large, somewhat triangular aperture bound in the front by the great wing of the sphenoid, behind by the apex of the petrous portion of the temporal bone, and medially by the body of the sphenoid and the basilar portion of the occipital bone. The nasal relations of the pituitary fossa are the crest of the sphenoid bone and the median, or perpendicular, plate of the ethmoid.

Since the introduction of the operating microscope in 1969 by Jules Hardy, the sublabial transseptal transsphenoidal approach to the pituitary has been the standard in the treatment of pituitary adenomas. However, improved endoscopes have led to development of endoscopic transnasal applications in many pituitary surgical centers (see Plate 1-31 ).

ANTERIOR PITUITARY HORMONES AND FEEDBACK CONTROL

The quantitative and temporal secretion of the pituitary trophic hormones is tightly regulated and controlled at three levels: (1) Adenohypophysiotropic hormones from the hypothalamus are secreted into the portal system and act on pituitary G-protein–linked cell surface membrane binding sites, resulting in either positive or negative signals mediating pituitary hormone gene transcription and secretion. (2) Circulating hormones from the target glands provide negative feedback regulation of their trophic hormones. (3) Intrapituitary autocrine and paracrine cytokines and growth factors act locally to regulate cell development and function. The hypothalamic-releasing hormones include growth hormone–releasing hormone (GHRH), corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH). The two hypothalamic inhibitory regulatory factors are somatostatin and dopamine, which suppress the secretion of growth hormone (GH) and prolactin, respectively. The six anterior pituitary trophic hormones—corticotropin (adrenocorticotropic hormone [ACTH]), GH, thyrotropin (thyroid-stimulating hormone [TSH]), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prolactin—are secreted in a pulsatile fashion into the cavernous sinuses and circulate systemically.

Hypothalamic–pituitary–target gland hormonal systems function in a feedback loop, where the target gland blood hormone concentration—or a biochemical surrogate—determines the rate of secretion of the hypothalamic factor and pituitary trophic hormone. The feedback system may be “negative,” in which the target gland hormone inhibits the hypothalamic–pituitary unit, or “positive,” in which the target gland hormone or surrogate increases the hypothalamic–pituitary unit secretion. These two feedback control systems may be closed loop (regulation is restricted to the interacting trophic and target gland hormones) or open loop (the nervous system or other factors influence the feedback loop). All hypothalamic–pituitary–target gland feedback loops are in part open loop—they have some degree of nervous system (emotional and exteroceptive influences) inputs that either alter the setpoint of the feedback control system or can override the closed-loop controls. Feedback inhibition to the hypothalamus and pituitary is also provided by other target gland factors. For example, inhibin, a heterodimeric glycoprotein product of the Sertoli cell of the testes and the ovarian granulosa cell, provides negative feedback on the secretion of FSH from the pituitary. Synthesis and secretion of gonadal inhibin is induced by FSH.

Blood levels of trophic and target gland hormones are also affected by endogenous secretory rhythms. Most hormonal axes have an endogenous secretory rhythm of 24 hours—termed circadian or diurnal rhythms —and are regulated by retinal inputs and hypothalamic nuclei. The retinohypothalamic tract affects the circadian pulse generators in the hypothalamic suprachiasmatic nuclei. Rhythms that occur more frequently than once a day are termed ultradian rhythms , and those that have a period longer than a day are termed infradian rhythms (e.g., menstrual cycle). Examples of circadian rhythms of pituitary and target gland hormones include the following: GH and prolactin secretion is highest shortly after the onset of sleep; cortisol secretion is lowest at 11 pm and highest between 2 and 6 am; and testosterone secretion is highest in the morning. In addition, GH, ACTH, and prolactin are also secreted in brief regular pulses, reflecting the pulsatile release of their respective hypothalamic releasing factors.

The circadian and pulsatile secretion of pituitary and target gland hormones must be considered when assessing endocrine function. For example, because of pulsatile secretion, a single blood GH measurement is not a good assessment of either hyperfunction or hypofunction of pituitary somatotropes; the serum concentration of the GH-dependent peptide insulinlike growth factor 1 (IGF-1)—because of its much longer serum half-life—provides a better assessment of GH secretory status. Circulating hormone concentrations are a function of circadian rhythms and hormone clearance rates; laboratories standardize the reference ranges for hormones based on the time of day. For example, the reference range for cortisol changes depending on whether it is measured in the morning or afternoon. Normal serum testosterone concentrations are standardized based on samples obtained from morning venipuncture. Disrupted circadian rhythms should clue the clinician to possible endocrine dysfunction—thus, the loss of circadian ACTH secretion with high midnight concentrations of cortisol in the blood and saliva is consistent with ACTH-dependent Cushing syndrome.

POSTERIOR PITUITARY GLAND

The posterior pituitary is neural tissue and is formed by the distal axons of the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) of the hypothalamus. The axon terminals store neurosecretory granules that contain vasopressin and oxytocin—both are nonapeptides consisting of a six–amino acid ring with a cysteine-to-cysteine bridge and a three–amino acid tail. In embryogenesis, neuroepithelial cells of the lining of the third ventricle migrate laterally to and above the optic chiasm to form the SON and to the walls of the third ventricle to form the PVN. The blood supply for the posterior pituitary is from the inferior hypophysial arteries, and the venous drainage is into the cavernous sinus and internal jugular vein.

The posterior pituitary serves to store and release vasopressin and oxytocin. The posterior pituitary stores enough vasopressin to sustain basal release for approximately 30 days and to sustain maximum release for approximately 5 days. Whereas approximately 90% of the SON neurons produce vasopressin, and all its axons end in the posterior pituitary, the PVN has five subnuclei that synthesize other peptides in addition to vasopressin (e.g., somatostatin, corticotropin-releasing hormone, thyrotropin-releasing hormone, and opioids). The neurons of the PVN subnuclei project to the median eminence, brainstem, and spinal cord. The major stimulatory input for vasopressin and oxytocin secretion is glutamate, and the major inhibitory input is γ-aminobutyric acid (GABA). When a stimulus for secretion of vasopressin or oxytocin acts on the SON or PVN, an action potential is generated that propagates down the long axon to the posterior pituitary. The action potential triggers an influx of calcium that causes the neurosecretory granules to fuse with the cell membrane and release the contents of the neurosecretory granule into the perivascular space and subsequently into the fenestrated capillary system of the posterior pituitary.

The stored vasopressin in neurosecretory granules in the posterior pituitary produces a bright signal on T1-weighted magnetic resonance imaging (MRI)—the “posterior pituitary bright spot.” The posterior pituitary bright spot is present in most healthy individuals and is absent in individuals with central diabetes insipidus. In addition, this bright spot may be located elsewhere in individuals with congenital abnormalities such that the posterior pituitary is undescended—it may appear at the base of the hypothalamus or along the pituitary stalk. Although posterior pituitary function is usually intact, this “ectopic posterior pituitary” may be associated with a hypoplastic anterior pituitary gland and with varying degrees of anterior pituitary dysfunction.

MANIFESTATIONS OF SUPRASELLAR DISEASE

Suprasellar lesions that may lead to hypothalamic dysfunction include craniopharyngioma, dysgerminoma, granulomatous diseases (e.g., sarcoidosis, tuberculosis, Langerhans cell histiocytosis), lymphocytic hypophysitis, metastatic neoplasm, suprasellar extension of a pituitary tumor, glioma (e.g., hypothalamic, third ventricle, optic nerve), sellar chordoma, meningioma, hamartoma, gangliocytoma, suprasellar arachnoid cyst, and ependymoma.

Endocrine and nonendocrine sequelae are related to hypothalamic mass lesions. Because of the proximity to the optic chiasm, hypothalamic lesions are frequently associated with vision loss. An enlarging hypothalamic mass may also cause headaches and recurrent emesis. The hypothalamus is responsible for many homeostatic functions such as appetite control, the sleep–wake cycle, water metabolism, temperature regulation, anterior pituitary function, circadian rhythms, and inputs to the parasympathetic and sympathetic nervous systems. The clinical presentation is more dependent on the location within the hypothalamus than on the pathologic process. Mass lesions may affect only one or all of the four regions of the hypothalamus (from anterior to posterior: preoptic, supraoptic, tuberal, and mammary regions) or one or all of the three zones (from midline to lateral: periventricular, medial, and lateral zones). For example, hypersomnolence is a symptom associated with damage to the posterior hypothalamus (mammary region) where the rostral portion of the ascending reticular activating system is located. Patients with lesions in the anterior (preoptic) hypothalamus may present with hyperactivity and insomnia, alterations in the sleep–wake cycle (e.g., nighttime hyperactivity and daytime sleepiness), or dysthermia (acute hyperthermia or chronic hypothermia).

The appetite center is located in the ventromedial hypothalamus, and the satiety center is localized to the medial hypothalamus. Destructive lesions involving the more centrally located satiety center lead to hyperphagia and obesity, a relatively common presentation for patients with a hypothalamic mass. Destructive lesions of both of the more laterally located feeding centers may lead to hypophagia, weight loss, and cachexia.

Destruction of the vasopressin-producing magnocellular neurons in the supraoptic and paraventricular nuclei in the tuberal region of the hypothalamus results in central diabetes insipidus (DI) (see Plate 1-27 ). In addition, DI may be caused by lesions (e.g., high pituitary stalk lesions) that interrupt the transport of vasopressin through the magnocellular axons that terminate in the pituitary stalk and posterior pituitary. Polydipsia and hypodipsia are associated with damage to central osmoreceptors located in anterior medial and anterior lateral preoptic regions. The impaired thirst mechanism results in dehydration and hypernatremia.

Anterior pituitary function control emanates primarily from the arcuate nucleus in the tuberal region of the hypothalamus. Thus, lesions that involve the floor of the third ventricle and median eminence frequently result in varying degrees of anterior pituitary dysfunction (e.g., secondary hypothyroidism, secondary adrenal insufficiency, secondary hypogonadism, and growth hormone deficiency).

Hypothalamic hamartomas, gangliocytomas, and germ cell tumors may produce peptides normally secreted by the hypothalamus. Thus, patients may present with endocrine hyperfunction syndromes such as precocious puberty with gonadotropin-releasing hormone expression by hamartomas; acromegaly or Cushing syndrome with growth hormone–releasing hormone expression or corticotropin-releasing hormone expression, respectively, by hypothalamic gangliocytomas; and precocious puberty with β-human chorionic gonadotropin (β-hCG) expression by suprasellar germ cell tumors.

Because of the close microanatomic continuity of the hypothalamic regions and zones, patients with suprasellar disease typically present with not one but many of the dysfunction syndromes discussed.

CRANIOPHARYNGIOMA

Craniopharyngioma is the most common tumor found in the region of the pituitary gland in children and adolescents and constitutes about 3% of all intracranial tumors and up to 10% of all childhood brain tumors. Craniopharyngiomas—histologically benign epithelioid tumors arising from embryonic squamous remnants of Rathke pouch—may be large (e.g., >6 cm in diameter) and invade the third ventricle and associated brain structures. This tumorous process is usually located above the sella turcica, depressing the optic chiasm and extending up into the third ventricle. Less frequently, craniopharyngiomas are located within the sella, causing compression of the pituitary gland and frequently eroding the boney confines of the sella turcica. Signs and symptoms—primarily caused by mass effect—typically occur in the adolescent years and rarely after age 40 years. The mass effect symptoms include vision loss by compression of the optic chiasm; diabetes insipidus by invasion or disruption of the hypothalamus or pituitary stalk; hypothalamic dysfunction (e.g., obesity with hyperphagia, hypersomnolence, disturbance in temperature regulation); various degrees of anterior pituitary insufficiency (e.g., growth hormone deficiency with short stature in childhood, hypogonadism, adrenal insufficiency, hypothyroidism); hyperprolactinemia caused by compression of the pituitary stalk or damage to the dopaminergic neurons in the hypothalamus; signs and symptoms of increased intracranial pressure (e.g., headache, projectile emesis, papilledema, optic atrophy); symptoms of hydrocephalus (e.g., mental dullness and confusion) when large tumors obstruct the flow of cerebrospinal fluid; and cranial nerve palsies caused by cavernous sinus invasion.

The findings on radiologic imaging are quite characteristic. Plain skull radiographs and computed tomography (CT) show irregular calcification in the suprasellar region. Magnetic resonance imaging (MRI) typically shows a multilobulated cystic structure that is usually suprasellar in location, but it may also appear to arise from the sella. The cystic regions are usually filled with a turbid, cholesterol-rich, viscous fluid. The walls of the cystic and solid components are composed of whorls and cords of epithelial cells separated by a loose network of stellate cells. If there are intercellular epithelial bridges and keratohyalin, the tumor is classified as an adamantinoma.

Treatment options for patients with craniopharyngiomas include observation, endonasal transsphenoidal surgery for smaller intrasellar tumors, craniotomy for larger suprasellar tumors, stereotactic radiotherapy, or a combination of these modalities. Most of these treatment approaches result in varying degrees of anterior or posterior pituitary hormone deficits (or both). In addition, recurrent disease after treatment is common (∼40%) because of tumor adherence to surrounding structures, and long-term follow-up is indicated.